Drosophila will be used as a model system to study the molecular mechanisms of muscle formation. Many of the key genes and processes involved in vertebrate muscle formation are largely conserved between vertebrates and Drosophila. Thus, the insights that we gain into Drosophila myogenesis should apply to humans and lead to breakthroughs in treating and/or preventing muscle-related diseases, which afflict an estimated 1,000,000 U.S. citizens.Two genes, irreC and kirre, provide powerful genetic tools for studying muscle formation. These genes are required for muscle precursors (myoblasts) to fuse to one another to generate multinucleated muscles. Previous data have shown that Kirre is expressed on the surface of a single subclass of myoblasts, called founders, where it attracts and facilitates the adhesion of a second subclass, called fusion competent cells. irreC, which is genetically redundant with kirre during muscle development, presumably acts in a similar role. The fusion competent cells recognize IrreC and Kirre through unknown receptors on their surface. These interactions lead to the formation of prefusion complexes between the two myoblast subclasses and, ultimately, to their fusion. Little is known about the mechanisms whereby myoblast adhesion leads to the formation of prefusion complexes. The goal of the proposed experiments is to identify the proteins that interact with Kirre and IrreC in the fusion pathway and to determine their molecular functions. Molecular, cell biological, and genetic techniques will be used to identify and characterize the receptor(s) for Kirre and IrreC, as well as putative downstream effectors that carry the signal inside the cell to initiate the fusion process. The identification of the other proteins in the Kirre and IneC pathway(s) will provide insights into the molecular mechanisms by which myoblasts fuse and lead to a more complete understanding of muscle formation.